Invasive species control is important for ecological and agricultural management. Genetic methods can provide species specificity for population control. We developed heritable maternal effect embryo lethality (HMEL), a novel strategy allowing negative population pressure from HMEL individuals to be transmitted within a population across generations. We demonstrate the HMEL technique in zebrafish through genome-integrated CRISPR/Cas targeted mutagenic disruption of nucleoplasmin 2b (npm2b) , a female-specific essential maternal effect gene, causing heritable sex-limited disruption of reproduction. HMEL -induced high-efficiency mutation of npm2b in females suppresses population, while males transmit the HMEL allele across generations. HMEL could be easily modified to target other genes causing sex-specific sterility, or generalized to control invasive fish or other vertebrate species for environmental conservation or agricultural protection.